The alveolar macrophage (AM) is a major regulator of the fibrotic response in the human lung. Previous work in our laboratories has shown that stimulated human AM and blood monocytes (BM) elaborate a soluble factor(s) that inhibits the log phase growth of lung fibroblasts. This factor(s) is between 16 and 24 KD molecular weight and its effect appears to be, at least partially, mediated by fibroblast prostaglandin (PG) elaboration. The aim of this proposal is to further our understanding of this monocyte/macrophage derived growth inhibitory factor(s) (MDGIF). Sequential studies are planned to address four questions. 1. What is MDGIF?: To address this question, we will: a) Further characterize MDGIF using gel filtration, anion exchange, cation exchange and reverse phase chromatography and chromatofocusing; b) characterize the relationship(s) between MDGIF and known fibroregulatory cytokines such as Interleukin-1 (alpha and beta), tumor necrosis factor-alpha, and gamma and beta interferon; c) if the factor(s) is unique, it will be purified to homogeneity. Attempts will also be made to obtain large enough quantities of the factor(s) for preparation of antisera. This will be done with bulk culture techniques and/or by screening transformed macrophage lines. 2. What modulates the release of and target cell response to MDGIF? The importance of lymphokines (such as gamma interferon), arachidonic acid metabolites, macrophage maturation and corticosteroids as regulators of the elaboration of and target cell response to MDGIF will be assessed. 3. Does MDGIF regulate other aspects of the fibrotic response? The effect of MDGIF on lung fibroblast collagen, collagen subtype and glycosaminoglycans (GAG) biosynthesis and the proliferation of quiescent lung fibroblasts will be assessed. 4. What is the mechanism of the effect of MDGIF on fibroblast growth? The importance of fibroblast prostaglandin and cyclic AMP production will be investigated. Studies will also be undertaken to characterize the cell cycle kinetics of the effect and to determine if MDGIF acts by preventing the fibroblasts' acquisition of competence, subsequent cell progression, or both. Once this is known, attempts will be made to determine if the inhibitory effect is the result of an alteration at the level of the receptor (altered expression/binding or tyrosine phosphorylation) or at the level of genetic expression (altered protooncogene activation).